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. 2018 Jul 3;8(1):57.
doi: 10.1186/s13550-018-0401-9.

PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects

Erica M Richards  1 , Paolo Zanotti-Fregonara  2 , Masahiro Fujita  3 , Laura Newman  3 , Cristan Farmer  3 , Elizabeth D Ballard  3 , Rodrigo Machado-Vieira  3   4 , Peixiong Yuan  3 , Mark J Niciu  3 , Chul Hyoung Lyoo  5 , Ioline D Henter  3 , Giacomo Salvadore  6 , Wayne C Drevets  6 , Hartmuth Kolb  6 , Robert B Innis  3 , Carlos A Zarate Jr  3
Affiliations

PET radioligand binding to translocator protein (TSPO) is increased in unmedicated depressed subjects

Erica M Richards et al. EJNMMI Res. .

Abstract

Background: Inflammation is associated with major depressive disorder (MDD). Translocator protein 18 kDa (TSPO), a putative biomarker of neuroinflammation, is quantified using positron emission tomography (PET) and 11C-PBR28, a TSPO tracer. We sought to (1) investigate TSPO binding in MDD subjects currently experiencing a major depressive episode, (2) investigate the effects of antidepressants on TSPO binding, and (3) determine the relationship of peripheral and central inflammatory markers to cerebral TSPO binding. Twenty-eight depressed MDD subjects (unmedicated (n = 12) or medicated (n = 16)) and 20 healthy controls (HC) underwent PET imaging using 11C-PBR28. Total distribution volume (VT, proportional to Bmax/Kd) was measured and corrected with the free fraction in plasma (fp). The subgenual prefrontal cortex (sgPFC) and anterior cingulate cortex (ACC) were the primary regions of interest. Peripheral blood samples and cerebrospinal fluid were analyzed to investigate the relationship between TSPO binding and peripheral and central inflammatory markers, including interleukins and neurotrophic factors previously linked to depression.

Results: TSPO binding was higher in MDD versus HC in the sgPFC (Cohen's d = 0.64, p = .038, 95% CI 0.04-1.24) and ACC (d = 0.60, p = .049, 95% CI 0.001-1.21), though these comparisons missed the corrected threshold for statistical significance (α = .025). Exploratory analyses demonstrated that unmedicated MDD subjects had the highest level of TSPO binding, followed by medicated MDD subjects, who did not differ from HC. TSPO binding correlated with interleukin-5 in cerebrospinal fluid but with no other central inflammatory markers.

Conclusions: This study found a trend towards increased TSPO binding in the brains of MDD subjects, and post hoc analysis extended these findings by demonstrating that this abnormality is significant in unmedicated (but not medicated) MDD subjects.

Keywords: Biomarkers; Inflammation; Major depressive disorder; Peripheral benzodiazepine receptor; Positron emission tomography.

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Conflict of interest statement

Ethics approval and consent to participate

This study was approved by the Combined Neuroscience Institutional Review Board of the National Institutes of Health. All participants gave written informed consent before entry into the study.

Competing interests

Drs. Salvadore, Drevets, and Kolb are full-time employees and shareholders of Janssen Pharmaceuticals, Inc. Dr. Zarate is listed as a co-inventor on a patent for the use of ketamine in major depression and suicidal ideation; as a co-inventor on a patent for the use of (2R,6R)-hydroxynorketamine, (S)-dehydronorketamine, and other stereoisomeric dehydro and hydroxylated metabolites of (R,S)-ketamine metabolites in the treatment of depression and neuropathic pain; and as a co-inventor on a patent application for the use of (2R,6R)-hydroxynorketamine and (2S,6S)-hydroxynorketamine in the treatment of depression, anxiety, anhedonia, suicidal ideation, and post-traumatic stress disorders. He has assigned his patent rights to the US government but will share a percentage of any royalties that may be received by the government. All other authors have no conflict of interest to disclose, financial or otherwise.

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Figures

Fig. 1
Fig. 1
Translocator protein (TSPO) binding in the subgenual prefrontal cortex (sgPFC) (a) and anterior cingulate cortex (ACC) (b) in individuals with a major depressive disorder (MDD) (n = 28) and healthy controls (n = 20). Groups are compared using ANCOVA, controlling for genotype
Fig. 2
Fig. 2
Translocator protein (TSPO) binding in the subgenual prefrontal cortex (sgPFC) (a) and anterior cingulate cortex (ACC) (b) among healthy controls and medicated and unmedicated patients with a major depressive disorder (MDD). Groups are compared using ANCOVA, controlling for genotype
Fig. 3
Fig. 3
Statistical significance maps rendered on axial slices and semi-inflated surface showing increase in 11C-PBR28 binding in unmedicated depressed patients compared to healthy controls (a). b The same analysis is restricted to high-affinity binder subjects, done with the more stringent threshold of p < 0.001. Only clusters with threshold p < 0.05 for cluster-wise multiple comparisons are displayed. The color bar represents T values. The same comparison using only mixed-affinity binders yielded no significant differences, but the unmedicated group comprised only two mixed-affinity binders
See this image and copyright information in PMC

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